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Synthesis and Stereochemical Determination of the Peptide Antibiotic Novo29

Year: 2023

Type: article

Abstract: High Resolution Image Download MS PowerPoint Slide This paper describes the synthesis and stereochemical determination of Novo29 (clovibactin), a new peptide antibiotic that is related to teixobactin and is active against Gram-positive bacteria. Novo29 is an eight-residue depsipeptide that contains the noncanonical amino acid hydroxyasparagine of hitherto undetermined stereochemistry in a macrolactone ring. The amino acid building blocks Fmoc-(2 R,3 R )-hydroxyasparagine-OH and Fmoc-(2 R,3 S )-hydroxyasparagine-OH were synthesized from ( R, R )- and ( S, S )-diethyl tartrate. Novo29 and epi -Novo29 were then prepared by solid-phase peptide synthesis using these building blocks. Correlation with an authentic sample of Novo29 through 1 H NMR spectroscopy, LC-MS, and in vitro antibiotic activity established that Novo29 contains (2 R,3 R )-hydroxyasparagine. X-ray crystallography reveals that epi -Novo29 adopts an amphiphilic conformation, with a hydrophobic surface and a hydrophilic surface. Four sets of epi -Novo29 molecules pack in the crystal lattice to form a hydrophobic core. The macrolactone ring adopts a conformation in which the main-chain amide NH groups converge to create a cavity, which binds ordered water and acetate anion. The amphiphilic conformation of epi -Novo29 is reminiscent of the amphiphilic conformation adopted by the related antibiotic teixobactin and its derivatives, which contains a hydrophobic surface that interacts with the lipids of the bacterial cell membrane and a hydrophilic surface that interacts with the aqueous environment. Molecular modeling suggests that Novo29 can adopt an amphiphilic conformation similar to teixobactin, suggesting that Novo29 may interact with bacteria in a similar fashion to teixobactin.

Source: The Journal of Organic Chemistry

DOI: 10.1021/acs.joc.2c02648